This application supports the career development of Brian Poligone, MD, PhD. who has an interest in the molecular signaling of NF-KB and its effect on the skin. The transcription factor NF-KB provides a regulatory on/off switch for gene expression that is important for inflammation and carcinogenesis. By understanding the role of NF-KB in the biology of keratinocytes and cutaneous lymphoid cells, inflammatory skin diseases and cancers may be better understood. We have constructed a novel mouse model to examine the NF-KB pathway in skin. The homozygous p65 S276D (PD) knock-in mouse contains a mutant form of NF-KB that increases the basal transcriptional activation of NF-KB dependent genes. Because studies on NF-KB activity in the skin have been underrepresented, detailed examination of the PD mouse should help clarify this central mediator of inflammation and tumorigenesis. Transcription factors are proteins that are the main on/off switch in regulating gene expression. NF-KB is a transcription factor that is known to be a central regulator of both inflammatory and oncogenic processes. Studying NF-KB in genetically engineered mouse models helps to clarify the role of NF-KB and allows a better understanding of its activity in inflammatory disease and cancer and ultimately may lead to improved patient care. RELEVANCE (See instructions): By understanding the basic mechanisms that lead to both skin inflammation and tumorigenesis, better treatments for skin disease are possible. It is through this basic understanding of skin disease that better treatments of can be identified.